The tetra and hexahydrodibenzofuran ring systems are common in biologically active natural compounds (Toth, J. E., et al. J. Org. Chem. 1987, 52, 473). Analogs containing these structural features have been studied for a variety of indications, such as: antipsychotics (Busch, N., et al. French Patent 2 482 966, 1981), analgesics (Skaletzky, L. L. U.S. Pat. No. 3,317,527, 1967), antitussives (Matharu, S. S.; et al. J. Med. Chem. 1977, 20, 197), CNS stimulants (Skaletzky, L. L. U.S. Pat. No. 3,317,527, 1967), and antiemetics (Youssefyeh, R. D., et al. J. Med. Chem. 1992, 35, 895).
Methods for obtaining these ring systems therefore are of considerable interest. Among the reported compounds which have valuable antiemetic and antipsychotic properties is 4-[N-(1-azabicyclo[2.2.2]octan-3-yl)]-2-chloro[5a,6,7,8,9,9a-hexahydro]dib enzofurancarboxamide. This racemic compound has eight possible stereoisomers, and it has been reported that 4-[N-(1-azabicyclo-[2.2.2]octan-3(S)-yl]-2-chloro-[5a(S)-9a(S)-(5a,6,7,8,9 ,9a-hexahydro)]-dibenzofurancarboxamide is the most active of the isomers. This is shown by Formula I. ##STR1##
The compound of Formula I is prepared by the reaction of 2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid with 3-aminoquinuclidine and is described in U.S. Pat. No. 4,863,921.